Small-molecule contraceptive decreases sperm motility in mice

Scientists have discovered a small molecule that prevents male mice from siring pups. The effects of this nonhormonal compound, known as CDD-2807, are reversible. Once the mice were off the compound, they were able to sire pups again. CDD-2807 targets serine/threonine-protein kinase 33 (STK33), an enzyme that’s enriched in testes. Because mutations in the gene that codes for STK33 have been linked to sterility in human men, the scientists hope CDD-2807 will lead to birth control that men can use.

A team led by Baylor College of Medicine’s Martin M. Matzuk screened billions of potential STK33 binders using DNA-encoded libraries. After finding an initial hit, the researchers changed the molecule’s structure until they arrived at CDD-2807, a compound that can inhibit STK33 at low nanomolar levels (Science 2024, DOI: 10.1126/science.adl2688).

When injected into the abdomens of male mice, CDD-2807 proved to be a potent contraceptive. “I was pretty amazed that even after 7 days we were starting to get decreases in motility of the sperm,” Matzuk says. In addition to affecting sperm’s ability to move, CDD-2807 caused changes in sperm morphology that were easy to spot with a microscope. “That is really important, especially when you’re thinking about clinical trials,” Matzuk says, because it would be easy to determine whether a drug candidate was effective by simply observing how it affects sperm’s motility and morphology.

CDD-2807 was also nontoxic to the mice. While it easily crosses the blood-testis barrier, it doesn’t get into the brain at appreciable levels. Matzuk tells C&EN that his team hopes to make analogs of CDD-2807 that could be taken as pills.

John K. Amory of the University of Washington, who studies contraception that could be marketed to men, says in an email that “this work represents a significant contribution to development of safe contraceptives.” He adds that he hopes “an oral formulation of this or a similar drug will prove safe in additional animal testing and can be studied in men soon for contraception.”